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Biomedical subjects

A Delacourte

Publications and source records attributed to A Delacourte.

At least 73 records · Page 4Linked to original sources
PubMed1996

Analysis of the APOE alleles impact in Down's syndrome.

Down's syndrome (DS) patients develop the characteristic features of Alzheimer's disease (AD) by their fourth decade, some of them exhibiting an AD-type dementia. We studied the apolipoprotein E (APOE) allele distribution in a population of 41 DS patients comprising 19.5% of demented, compared to 35 control subjects. No statistical difference was observed, but the epsilon2 allele may delay the age of dementia. As described in other studies, the impact of the different APOE alleles in DS is modest. However the compilation of all published studies on AD-type dementia in DS suggests that the epsilon2 allele has a protective effect. In delaying the age of onset, the epsilon2 allele would have a similar action in AD-type dementia in DS and in AD families with amyloid precursor protein (APP) mutations.

Aged↗
PubMed1996

Relevance of the quantification of apolipoprotein E in the cerebrospinal fluid in Alzheimer's disease.

Apolipoprotein E (Apo E), one of the major structural and functional apolipoproteins, has recently been implicated in the pathogenesis of Alzheimer's disease (AD). Several studies revealed that Apo E4 isoform is associated with the pathogenic process in AD. A significant reduction of cerebrospinal fluid (CSF) Apo E level in AD patients has been reported in two studies. To further investigate the physiopathological significance of such a variation of Apo E concentration in the CSF, we performed a quantification of Apo E by an enzyme linked immunosorbent assay (ELISA). There were no significant differences in CSF Apo E level between AD cases and control subjects or patients suffering from other neurological diseases. Gender, age and Apo E phenotype explained none of CSF Apo E concentration variability.

Aged↗
PubMed1996

Dephosphorylation studies of SKNSH-SY 5Y cell Tau proteins by endogenous phosphatase activity.

Recent data have shown that the microtubule-associated Tau proteins are phosphorylated but to a lesser extent than PHF-Tau proteins which are the major components of Alzheimer's disease paired helical filaments. These normal Tau proteins are highly sensitive to the endogenous phosphatase activity during post-mortem delay. In order to understand the basic equilibrium between phosphatase and kinase activities, phosphorylation and dephosphorylation mechanisms of Tau proteins were studied in neuroblastoma cells. The present results demonstrate that an endogenous phosphatase activity is present and directed on Tau proteins in the SKNSH-SY 5Y cell extracts. Interestingly, the okadaic acid-induced hyperphosphorylated Tau proteins are more resistant to the phosphatase activity than the control Tau proteins. Our data emphasize the value of this in vitro cellular model for the study of biological conditions that control Tau protein phosphorylation levels.

Enzyme Inhibitors↗
PubMed1996

Phorbol ester enhances phosphorylated tau protein immunoreactivity in neuronal cultures.

One of the hallmarks of Alzheimer's disease (AD) is neurofibrillary degeneration which results from the aggregation of phosphorylated tau proteins into paired helical filament (PHF) structures. AD2 is a new monoclonal antibody raised against PHF tau which detects neurofibrillary tangles in AD brain. In primary neuronal cultures, phorbol ester treatment induced a time- and dose-dependent increase in AD2 immunoreactivity quantified by laser confocal microscopy and immunoblottings. Alkaline phosphatase treatment reversed these immunocytochemical changes. These results suggest that the modifications of neuronal metabolism induced by phorbol ester including protein kinase C activation produce an increase in phosphorylated tau immunoreactivity.

Animals↗
PubMed1996

Apolipoprotein E in Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex: genotype analysis and relationships to neuropathological changes.

Apolipoprotein E (Apo E) has been recently identified within amyloid deposits and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients. A strong association of the Apo E epsilon 4 allele with higher risk of developing AD has also been reported. In the present study, the distribution of Apo E and the possible relationship between Apo E alleles and neuropathological alterations were analyzed in a series of Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) cases, a neurodegenerative condition characterized neuropathologically by widespread, severe neurofibrillary tangle formation but rare amyloid deposits. ApoE immunoreactivity was consistently observed in both type of lesions in these cases. Compared to tau protein immunoreactivity, there were generally fewer Apo E-immunoreactive neurofibrillary tangles, particularly in the deep layers of the neocortex and in the hippocampus. Genotype analysis revealed that the epsilon 4 allele frequency was 5.9%, the epsilon 3 allele frequency 88.2%, and the epsilon 2 allele frequency 5.9% in this series. Recent data suggest that the Apo E4 variant may induce amyloidogenesis, while E2 could have a neuroprotective role. However, the rare Guamanian patients with amyloid deposits in cortical areas were not related to the epsilon 4 allele, since all cases with senile plaques were epsilon 3/epsilon 3. In addition, compared to unaffected Guamanian cases and other Asian-Pacific populations previously reported, the observed low frequency of the epsilon 2 allele in the present cases, which may be consistent with the notion that this allele, may represent a neuroprotective factor in several neurodegenerative disorders. The present data indicate that there is a strong interaction between Apo E deposition and neurofibrillary changes in Guamanian ALS-PDC.

Aged↗
PubMed1996

Hyperphosphorylated tau proteins differentiate corticobasal degeneration and Pick's disease.

In neurodegenerative disorders, hyperphosphorylated tau proteins aggregate into abnormal filaments. In the present study, tau protein alterations were studied in one corticobasal degeneration and seven Pick's disease cases using specific immunological probes. The typical lesions of corticobasal degeneration and Pick's disease were revealed by immunohistochemistry, including the presence of Pick bodies and achromatic swollen neurons, neuritic alterations, and neurofibrillary tangles. Tau-immunoreactive glial tangles were also observed. By immunoblotting, the case of corticobasal degeneration was characterized by the tau profile previously reported to occur in progressive supranuclear palsy with an intense labeling of the two tau 64 and 69 bands, while tau 55 was not visualized. In Pick's disease cases with Pick bodies and neurofibrillary tangles, a tau triplet similar to that encountered in Alzheimer's disease (tau 55, 64 and 69) was detected. Furthermore, a particular tau profile was found in four Pick's disease cases showing only Pick bodies and no neurofibrillary tangles. In these cases, tau 55 and 64 were strongly immunoreactive, whereas tau 69 was almost unlabeled. These differences are likely to be related to particular pools of tau isoforms present within the degenerating neurons. Since there is a great diversity of neurodegenerative disorders with substantial clinical and neuropathological overlap, the electrophoretic profile of tau proteins could represent a useful marker for the type of neurodegeneration.

Aged↗
PubMed1996

AD2, a phosphorylation-dependent monoclonal antibody directed against tau proteins found in Alzheimer's disease.

Alzheimer's disease is characterized by an intraneuronal aggregation of hyperphosphorylated tau proteins into paired helical filaments. The hyperphosphorylation of tau proteins induces a decrease in their electrophoretic mobility, resulting in a pathological tau triplet referred to as tau 55, 64 and 69 or tau-PHF. We have developed monoclonal antibodies directed against this pathological tau triplet. In the present article, we report the properties of antibody AD2, which detects the hyperphosphorylated tau proteins forming paired helical filaments during Alzheimer's disease. Using immunoblotting, AD2 exclusively labeled the tau triplet, while normal tau proteins from control cases were not immunodetected. Furthermore, AD2 is highly specific in that it was able to detect the triplet not only in tau preparations but also in total brain homogenates from Alzheimer's disease patients. The binding of this monoclonal antibody to tau proteins is phosphorylation dependent. Characterization of this antibody allowed us to identify its epitope as containing phosphorylated Ser-396 with the participation of phosphorylated Ser-404. AD2 was also shown to label normal tau proteins from rapidly processed brain tissues, but its epitope is rapidly dephosphorylated during postmortem intervals. However, in autopsic brains, AD2 still represents a valuable tool to investigate neurofibrillary degeneration at the biochemical and immunocytochemical levels.

Adolescent↗
PubMed1996

Specific pathological Tau protein variants characterize Pick's disease.

Pick's disease (PiD) is characterized by a pan-laminar frontotemporal cortical atrophy, widespread degeneration of the white matter, chromatolytic neurons, and Pick bodies (PB). Microtubule-associated Tau proteins are the main cytoskeletal components modified during the neurodegenerative changes. In the present study, pathological alterations of Tau proteins were investigated in the brains of five PiD cases at both neuropathological and biochemical levels, using the monoclonal antibody AD2 which recognizes a phosphorylation-dependent Tau epitope and strongly labeled PB. A large number of cortical and subcortical regions were studied on frozen materials. Tau proteins were analyzed on mono- and two-dimensional gel electrophoreses using a quantitative western blot approach. In all specimens, a 55 and 64 kDa Tau doublet was observed in limbic, frontal, and temporal cortices as well as in striatum and substantia nigra. In contract, Alzheimer's disease (AD) brains are characterized by the presence of the 55, 64, and 69 kDa Tau triplet whereas the 64 and 69 kDa doublet is more typical of the progressive supranuclear palsy and corticobasal degeneration. Thus, the 55 and 64 kDa doublet appears to be specific to PiD, less acidic than AD Tau proteins, and well correlated with the presence of PB.

Aged↗
PubMed1996

Specific tau variants in the brains of patients with myotonic dystrophy.

The mutation causing myotonic dystrophy (DM) is an unstable CTG trinucleotide repeat in a gene encoding for a protein with putative serine-threonine kinase activity. Several studies have reported the appearance of abnormally frequent neurofibrillary tangles (NFTs) in the cortex of patients with DM. Using immunologic probes against normal and pathologic hyperphosphorylated tau proteins, the basic components of NFTs, we performed a biochemical and immunohistochemical study of the brains of two DM cases. We compared the tau profiles with those found in Alzheimer's disease (AD) using mono- and two-dimensional immunoblotting. Patients were aged 53 and 61 years at death. In both cases, we observed few perikaryal and axonal inclusions in the hippocampus as well as the entorhinal and inferior temporal cortices. As in AD brain homogenates, pathologic tau proteins, named tau 55, 64, and 69, were exclusively immunodetected in the DM cases in the hippocampus, the entorhinal cortex, and in most of the temporal areas. Amounts of pathologic tau proteins were higher in the more severely affected case, but lower than in AD brain homogenates. Pathologic tau proteins were less acidic in DM than in AD. We found a very low amount of the tau 69 isoform in DM extracts, and in most of the cortical areas, tau 55 was overexpressed compared with AD homogenates. A link between the increase of kinase activity and the presence of pathologic tau proteins is discussed.

Brain↗
PubMed1995

Evidence for apolipoprotein E epsilon 4 association in early-onset Alzheimer's patients with late-onset relatives.

Recently several reports have extended the apolipoprotein E (APOE) epsilon 4 association found in late-onset Alzheimer's disease (LOAD) patients to early-onset (EO) AD patients. We have studied this question in a large population of 119 EOAD patients (onset < or = 60 years) in which family history was carefully assessed and in 109 controls. We show that the APOE epsilon 4 allele frequency is increased only in the subset of patients who belong to families where LOAD secondary cases are present. Our sampling scheme permits us to demonstrate that for an individual, bearing at least one epsilon 4 allele increases both the risk of AD before age 60 and the probability of belonging to a family with late-onset affected subjects. Our results suggest that a subset of EOAD cases shares a common determinism with LOAD cases.

Adult↗
PubMed1995

Isoelectric point differentiates PHF-tau from biopsy-derived human brain tau proteins.

In the present study, Tau proteins were detected by two monoclonal antibodies AD2 and Tau-1 raised against PHF-tau and normal Tau proteins respectively using single- and two-dimensional immunoblotting. We demonstrate here the presence of a Tau triplet in brain homogenates from patients with Alzheimer's disease (AD) processed human brain biopsies from controls. However PHF-tau proteins have a slight but significantly higher mol. wt and a much more acidic isoelectric point. Therefore, Tau proteins are more phosphorylated in AD.

Adult↗
PubMed1995

Quantitation of Alzheimer's amyloid peptide and identification of related amyloid proteins by dot-blot immunoassay.

In Alzheimer's disease, the main component of amyloid deposits is a 39-43 amino acid peptide referred to as amyloid peptide or A beta. A crucial issue in the study of this disorder is to define the sequence of events that lead to amyloid deposition. In the present study, a new approach was developed that allows to specifically solubilize A beta peptide trapped within amyloid deposits and to quantify its amount by dot-blot immunoassay. The present method also permits to isolate components tightly bound to A beta and that are likely to catalyze its aggregation. Biochemical A beta quantitation was performed in 4 Brodmann areas from 17 elderly individuals exhibiting different degrees of amyloidosis. In parallel, classical neuropathology was done by histochemical and immunohistochemical methods. A beta amounts (pmol) were correlated to the number of amyloid deposits determined by neuropathology showing high statistical significance. Moreover, amyloid-binding proteins including apolipoprotein E and heparan sulfate proteoglycans were also found associated to A beta in the amyloid preparation. The present biochemical procedure is a new and reliable method to quantify amyloid deposition in brain. Furthermore, it allows to detect amyloid-associated components such as apolipoprotein E, that may be involved in the pathological process of amyloidogenesis.

Aged↗
PubMed1995

New immunoassay for the mapping of neurofibrillary degeneration in Alzheimer's disease using two monoclonal antibodies against human paired helical filament tau proteins.

Monoclonal antibodies against human paired helical filament tau (PHF-tau) proteins were produced. Two of these antibodies, AD1 and AD2, were shown by immunoblot to be directed against distinct hyperphosphorylated epitopes of the PHF-tau proteins. Using AD1 and AD2, an antigen-capture ELISA specific for PHF-tau proteins was developed and used to map the neurofibrillary degeneration of several Broadmann areas from an Alzheimer's disease patient. The results confirm that the neurofibrillary degeneration predominates in parietal and temporal lobes.

Aged↗
PubMed1995

Shift from fetal-type to Alzheimer-type phosphorylated Tau proteins in SKNSH-SY 5Y cells treated with okadaic acid.

Tau proteins are abnormally phosphorylated in Alzheimer's disease. Pathological Tau proteins named PHF-Tau 55, PHF-Tau 64, and PHF-Tau 69, are the main constituents of the paired helical filaments (PHF). When treating SKNSH-SY 5Y cells with okadaic acid (OA), Tau 55 protein was clearly induced whereas Tau 64 protein was only faintly induced. Here, we show that the absence of Tau 69 could be explained by the fact that adult isoforms containing N-terminal inserts are not detected. Phosphorylation is similar for untreated cellular Tau proteins and fetal Tau proteins, while OA cell treatment transformed fetal-type into Alzheimer-type phosphorylated proteins.

Adult↗
PubMed1995

Immunogold labelling of paired helical filaments and amyloid fibrils by specific monoclonal and polyclonal antibodies.

Senile plaque and paired helical filament (PHF) formation are characteristic of Alzheimer's disease, but the mechanisms leading to these lesions still remain unclear. To understand them better, we have performed different immunolabellings of amyloid protein and PHF. We describe a very specific immunodetection of PHF with AD2, a monoclonal antibody directed against a hyperphosphorylated epitope of PHF-tau, and use double immunolabelling to show that PHF and plaque amyloid are discretely labelled by different antibodies. We also discuss different mechanisms of PHF maturation.

Aged↗
PubMed1995

Cortical mapping of Alzheimer pathology in brains of aged non-demented subjects.

1. The presence of Alzheimer-type neurofibrillary pathology and amyloid deposits within the brains of 27 aged non-demented subjects was investigated by immunoblotting and immunohistochemistry using antibodies directed against pathological Tau proteins 55, 64 and 69 and beta A4 respectively. 2. The abnormal Tau triplet, a biochemical marker of neurofibrillary degeneration was quantified by western blot and densitometric analysis in several cortical areas including the entorhinal cortex (EC), hippocampus and Brodmann areas (BA) 38, 20, 22, 35, 9, 44 and 39. 3. The abnormal Tau triplet was detected in the EC and the hippocampus of most of the controls aged over 70 years. In few control cases abnormal Tau proteins were also detected in the isocortex, in BA38 alone or also in BA20. Some cases and especially those with Tau pathology in the temporal lobe contained numerous senile plaques (SP) in the neocortex. 4. The authors conclude that control cases with Tau pathology in the temporal lobe and numerous SP in the neocortex were likely to be subclinical stages of AD whereas others with Tau pathology exclusively detected in the EC and hippocampus and without or few SP in the neocortex were related to normal aging.

Aged↗
PubMed1995

Immunocytochemical characterization of Tau proteins during cerebral aging of the lemurian primate Microcebus murinus.

The immunocytochemistry of Tau proteins in the cortical pyramidal neurons of the adult microcebes has been studied, using antibodies against human normal and pathological Tau proteins. Some changes related to the age and to some pathologies were observed. In fact, during the adult life, Tau proteins appeared as very thin granulations scattered in the whole neuronal cytoplasm. With age, a part of these proteins aggregated and became like thick granules at the neuron periphery; the distribution was not uniform, and numerous neurons with aggregated Tau proteins were observed in amyloid plaque-containing brains. Abnormally phosphorylated Tau proteins were also observed in some aged animals, using an absorbed anti-PHF recognizing the pathological Tau proteins characteristic of Alzheimer's disease. This present work confirms that the microcebe is a good model for studying disfunctions involved in the normal cerebral aging and in some neurodegenerative disorders which affect humans.

Adult↗